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A Perfect Fit: Cancer Medicines Get Personal(ized)

It was magical to see her transform folds of fabric into dresses, shirts or Halloween costumes. In my preteen years, I began to protest the measuring and fitting process. I didn’t like her pulling the frayed yellow measuring tape tight around my middle; I grumbled when the straight pins poked me as she adjusted a partly sewn garment. But my objections evaporated when the dressing room mirrors revealed time and again that my arms and legs had grown too long for the “standard” clothes in my size. Not so with the outfits grandma made for me. Each one was a perfect fit.

Can cancer treatments be tailored like clothing? Can the medicine be matched to “fit” each patient? Increasingly, the evidence is saying yes – cancer treatments can be tailored when tumors have specific genetic changes that are driving their growth, and when drugs exist that counteract those signals.

William Pao, M.D., Ph.D., is leading Vanderbilt-Ingram’s new Personalized Cancer Medicine Initiative.

Simply put, personalized oncology means “matching the right drug to the right patient at the right time,” says William Pao, M.D., Ph.D., who is leading the new Personalized Cancer Medicine Initiative at the Vanderbilt-Ingram Cancer Center.

Within the next year, Vanderbilt-Ingram aims to make personalized cancer medicine a routine part of clinical care. Starting with lung cancer and melanoma, Pao and his colleagues will wrap their genetic measuring tapes around every tumor – and select therapies that fit the specific genetic changes they find.

Off-the-rack treatments
Surely cancer care has always been personalized, you might be thinking. And to the extent possible, it has been. Oncologists take into account the patient’s characteristics and the cancer’s characteristics (tissue type, stage) to plan therapy.

But it’s not an exact science. Chemotherapy treatments are often a one-size-fits-all approach – sometimes they work, and sometimes they don’t. In general, patients receive a course of chemotherapy and then wait – up to six weeks or longer – to find out if the drug is having an effect. If it doesn’t appear to be killing the cancer cells, the doctor and patient will decide on another treatment option. In the meantime, the patient may have suffered the unpleasant side effects of chemotherapy, without any benefit.

Rita Quigley knows this approach first-hand.

In the summer of 2007, she noticed a small bump, the size of a mosquito bite, under the skin on her upper arm. She mentioned it to the dermatologist she was routinely seeing because of a malignant melanoma (skin cancer) that had been removed from her back 17 years earlier. There was nothing visible on the skin, and the dermatologist had trouble even feeling the bump, Quigley recalls. Her family physician suggested it might be a sebaceous cyst.

Quigley requested that the mass be removed. The pathology report came back with ominous news: melanoma.

CT and PET imaging scans revealed that she had tumors in her lungs, and Quigley’s Huntsville, Ala., oncologist referred her to Jeffrey Sosman, M.D., director of Vanderbilt-Ingram’s Melanoma Program.

Malignant melanoma that has metastasized to distant sites in the body is notoriously difficult to treat.

“Melanoma has been the most frustrating of solid tumors,” Sosman says. “There have been some positive results with various therapies in a small minority of patients, but the great majority of patients do not respond to the chemotherapy or immunotherapy treatments that we have.”

Sosman opted to treat Quigley with the chemotherapy drug dacarbazine. She came to the clinic for an intravenous
infusion once every three weeks for three months, but the tumors in her lung didn’t shrink. She says she was fortunate to only suffer mild discomfort – achiness and flu-like symptoms – during the chemotherapy.

At the end of October 2007, thoracic surgeon Eric Lambright, M.D., at Vanderbilt-Ingram removed her lung tumors. The surgery was successful, and she recovered from it.

But a follow-up scan several months later showed new tumors in Quigley’s pelvic area, and Sosman decided to treat her with interleukin-2, an immunotherapy aimed at stimulating the patient’s immune system to kill the cancer. For the interleukin-2 treatment, Quigley was hospitalized for five days while the medicine was administered every eight hours around-the-clock through a central venous catheter. After one week of rest at home, the treatment was repeated. Hospitalization is required because the side effects of interleukin-2 treatment can be severe.

“Interleukin-2 is a different ballgame. It was several weeks after the second treatment before I felt like myself again,” Quigley says.

Six weeks after the treatment, imaging scans showed no tumor shrinkage.

It had now been a year since Quigley had noticed the bump on her arm. She had been through two surgeries, two grueling treatments, and still the cancer persisted.

But at this point a door opened for her – Sosman and his Vanderbilt-Ingram colleague Igor Puzanov, M.D., were studying a new drug in patients with metastatic melanoma. The study was a Phase I clinical trial, meaning that the drug had passed through pre-clinical (cell and animal) testing, but was just beginning to be tested in patients. The drug was not “off-the-rack” – instead it was tailored to a particular genetic change in tumor cells, and Quigley’s cancer had the genetic change. She enrolled in the trial.

Measuring cancer genes
To understand the experimental drug being offered to Quigley – and others like it – we need to back up.

For more than 30 years, cancer has been linked to genetic mutations that give cancer cells a growth and survival advantage. As the thinking goes, tumor formation involves multiple genetic mutations in a single cell – some that activate growth-enhancing genes (oncogenes) and others that inactivate growth-inhibitory genes (tumor suppressor genes).

Jeffrey Sosman, M.D., and colleagues are studying a new chemotherapy drug tailored for melanomas with a specific genetic alteration.

Recently, investigators and the pharmaceutical industry have aimed drug development efforts at these mutant gene products that contribute to cancer cell growth, with the hope that medicines “targeted” at these molecules will kill cancer cells without harming normal cells. But how likely is it that blocking just one target – when tumor cells often have many mutated genes – will kill the cancer?

Consider Gleevec. The drug bounded onto the world stage in 2001, with accelerated approval from the Food and Drug Administration for the treatment of chronic myelogenous leukemia (CML).

The genetic abnormality that causes CML – the so-called Philadelphia chromosome (named for the city in which it was discovered) – results from a translocation, a rearrangement that fuses two genes from different chromosomes together. One of the genes encodes a cellular signaling protein (ABL, a tyrosine kinase), which is usually turned “on” and “off” in a well-controlled manner. The rearrangement produces an abnormal protein (BCR-ABL), which is stuck in the “on” position and drives cells to become leukemic. Gleevec blocks the activity of the aberrant receptor, and kills the cancer cells.

The drug is effective in the overwhelming majority of CML patients with the Philadelphia chromosome, Pao notes.

“Gleevec is really the poster child of personalized cancer medicine,” he says. “There’s a genetic change that leads to an aberrant signaling protein and causes CML. You give the patients a pill that inhibits the activity of that protein, and the tumor cells go away.”

At about the time that Gleevec was starting to work in patients with CML, Pao was a research fellow in the laboratory
of Harold Varmus, M.D., at Memorial Sloan-Kettering Cancer Center. (Varmus and J. Michael Bishop, M.D., won the 1989 Nobel prize for their discoveries that oncogenes are actually cellular genes involved in normal cell growth and division, and that disturbances in these genes can lead to cancer.)

Pao and colleagues were exploring the same question that was being tested with Gleevec in CML – can tumors become so dependent on a single mutant growth-enhancing signaling protein that disrupting that signal kills the tumors? Their model was lung cancer. They had shown in mice that turning on a mutant oncogene in the lung caused lung tumors, and turning the oncogene off caused the tumors to die. The studies supported the concept of “oncogene addiction” – a phrase coined by the late Bernard Weinstein, M.D., to describe an apparent dependency of some cancers on one or just a few mutant genes.

As they worked to understand the molecular signaling in the mouse lung tumors, Pao and colleagues (and other investigators around the country) were also testing two targeted therapies – Iressa and Tarceva – in patients with lung cancer, the leading cause of cancer-related death in the United States.

The timing was fortuitous.

Most of the patients had no response to the drugs, but about 10 percent of the patients had a rapid and sometimes dramatic clinical response.

“In some patients, within five days we could see evidence of tumor shrinkage,” Pao recalls. “It looked just like this phenomenon of oncogene addiction that we were studying in the mice, and it said to us that these pills must be turning off something that’s critical for the tumor. We just had to figure out what that was.”

The Varmus group and others, including David Carbone, M.D., Ph.D., and colleagues at Vanderbilt-Ingram, focused on Iressa and Tarceva’s molecular target, the epidermal growth factor receptor (EGFR). They found activating mutations in the EGFR gene in lung tumor tissue from patients who responded to Iressa
or Tarceva.

Subsequent trials have shown that patients whose tumors have certain EGFR gene mutations have a 75 percent chance of having their tumors shrink when they are treated with EGFR-targeted medicines – oral pills with relatively mild side effects compared to chemotherapy. (These medicines are effective in only about 10 percent of “unselected” lung cancer patients.) By contrast, patients treated with standard chemotherapy have a 20 percent to 30 percent chance of tumor shrinkage, Pao says.

Pao and others have also identified genetic changes that predict that a patient will not respond to Iressa or Tarceva. And they have discovered changes that occur in tumors that are initially responsive but then become resistant to therapy.

Now the race is on, Pao says, to catalog the genetic defects in all kinds of cancers, discover which mutations are critical to tumor survival, and link those mutations to specific targeted therapies.

In the fitting room
In 2002, investigators reported that about 60 percent of melanomas contained a single mutation in a gene called BRAF. The BRAF protein functions in a cell growth signaling pathway, and the mutation activated the pathway and caused cells in culture to behave like tumor cells.

“Everyone who read that paper said, this is a target for melanoma – if we can target BRAF, we’re going to see Gleevec-like responses in melanoma,” Sosman recalls.

A drug called Nexavar targeted a related RAF protein and was already in clinical trials (and has since been approved) for kidney cancer. As a single agent in patients with melanoma that had resisted other therapies, it “didn’t do much of anything.” Another few drugs that worked in the same pathway, but not on BRAF, showed some activity, but the overall results were discouraging, Sosman says.

And then along came PLX4032, a BRAF inhibitor produced by Plexxikon and Roche Pharmaceuticals that in cultured cells specifically blocked the BRAF mutant most commonly found in melanoma. Puzanov led Vanderbilt’s participation in the Phase I trial (which has ultimately included six centers).

In this PET scan, dense black spots in the chest and abdomen represent melanoma metastases before treatment (top) and after treatment with experimental “tailored” drug PLX4032 (bottom). Images courtesy of Jeffrey Sosman, M.D.

Initial results were not stellar, Sosman recalls, but a reformulation of the drug allowed the investigators to achieve higher doses and “all of a sudden, everybody started seeing responses.” He remembers the striking images that investigators at the various centers shared electronically.

“It was really stunning. Some of the patients were responding incredibly quickly, and we even saw symptomatic improvement – patients who were sick when they started, got the drug, and felt much better. That’s something I’ve never seen in treating patients with melanoma,” Sosman says.

Rita Quigley started taking PLX4032 in August 2008. Her tumors have shrunk, and she continues to take the pills daily, with minimal side effects. She felt well enough to return to work as a part-time nurse in a pediatrics practice, after seeing her second of three daughters off to college.

She has the highest praise for Sosman and his colleagues and finds it “amazing that it’s a possibility” to have a medicine selected to fit her tumor.

“I feel very blessed; I’m very thankful,” Quigley says.

Puzanov presented initial findings from the Phase I trial at this year’s annual American Society of Clinical Oncology conference. Of 16 patients with BRAF-positive melanoma, more than half had their cancer shrink by at least 30 percent. Patients without the mutation had no response to the drug. The investigators have extended the Phase I trial to include additional patients, and they are preparing to launch Phase II studies, which will treat between 90 and 150 patients at 12 centers. Sosman is leading the Phase II trial.

“The world of melanoma treatment has changed,” Sosman says.

“It’s really very exciting to treat patients whose tumors have the right genetic profile with this drug and expect them to respond, and for the most part they do.”

The BRAF mutation targeted by the PLX drug also is present in other cancers, Sosman points out. It’s present in about 40
percent of thyroid cancers, 10 percent to 15 percent of colon cancers, and 3 percent to 6 percent of lung cancers. A trial under way in colon cancer patients with the mutation is showing response rates similar to the melanoma studies.

These findings highlight a shifting view of cancer – rather than being a disease known primarily by its tissue of origin (breast, colon, lung), it is moving to a disease classified by the genetic mutations that drive it. And this change has implications for therapy, Sosman notes.

“Cancers of the same genetic abnormalities should be treated the same whether they come from the skin or the colon or the lung,” he says. “I think that’s a concept that is really going to change our approach to treatment.”

This is the crux of the personalized oncology initiative that Pao is leading at Vanderbilt-Ingram – to put into place the systems that will allow physicians to routinely measure a tumor’s genetic changes and fit therapies to them.

Stitching the pieces together
Implementing a new clinical strategy requires the cooperation of multiple parts of the clinical enterprise, Pao points out, which could be an onerous task. But at Vanderbilt-Ingram, which he joined this year, Pao has found a culture of collaboration and “an openness to new ideas and trying new things that might improve patient care.”

With the aid of Cindy Vnencak-Jones, Ph.D., and colleagues in the Department of Pathology’s Clinical Molecular Genetics program, Pao is developing a platform to test for multiple genetic mutations at the same time.

The goal is to develop tests for between 30 and 50 mutations. Pao and colleagues are “mining” databases of reported mutations, in order to build melanoma- and lung cancer-specific panels. Tested mutations will have relevance with respect to existing or emerging targeted therapies. Later, they will develop panels to detect mutations specific to other cancer types.

The results of the tests will need to be integrated into the electronic medical record with algorithms that aid physicians in assigning therapies. Vanderbilt is a world leader in medical informatics, and Dan Masys, M.D., professor and chair of Biomedical Informatics at Vanderbilt, and his colleagues are working on the informatics needs.

“Many cancer centers are trying to move this kind of tumor genotyping and therapy planning forward, but the big question is how to do that in the most efficient manner,” Pao says. “I think that Vanderbilt has the right strengths to really make this happen.”

The initiative is being supported by the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation and an anonymous foundation. Foundation support is especially important, Pao says, because it is difficult to gain National Institutes of Health funding for “nuts and bolts” implementation efforts like this.

Ultimately, Pao thinks that using genetic measurements to guide therapy decisions will become routine, something that we won’t even call “personalized” anymore.

But he is quick to acknowledge that we’re not there yet.

We still need the results of ongoing efforts that are defining the genetic mutations in cancers – particularly those mutations to which tumors become “addicted,” Pao says. We need more and better drugs to hit those targets. We need to understand how tumors that initially respond to targeted medicines become resistant – something Pao and his colleagues have done for lung cancers that become resistant to Iressa or Tarceva – and use that information to identify new targets and new drugs.

Despite the hurdles, Pao is excited.

“The genetic alteration that causes CML – BCR-ABL – was discovered more than 30 years ago, but it wasn’t until the last decade that we had a drug that could be used in patients with that mutation,” he notes. In contrast, investigators identified a new genetic mutation (called EML4-ALK) in 5 percent of lung cancer patients just two years ago, and already a specific inhibitor has moved through Phase I trials with a 50 percent response rate in patients with the mutation.

“The pace of discovery is increasing and we’re going to be able in the next five to 10 years to routinely assign therapies based on the genetic makeup of patients’ tumors.”

Perfectly fitted therapies. My grandma would be pleased.

Trying on new cancer drugs

Lee Lange has a Nike-inspired message for patients who are on the fence about participating in a clinical trial: just do it.

Lange, who taught high school biology at Fort Campbell, Ky., for 37 years, sees his own participation – he’s currently taking part in his second study for patients with melanoma – as a positive contribution to science.

“I’m proud to do it,” says Lange, a patient of Jeffrey Sosman, M.D., director of the Melanoma Program at Vanderbilt-Ingram Cancer Center. “I’ll take any protocol I’m offered because I know that even if it doesn’t help me, the doctors are getting information that will help someone else down the line. And that’s what science is all about.”

“The willingness of patients to help themselves and others by participating in trials is so critical to our efforts to further clarify and improve the treatment of melanoma,” Sosman says.

Vanderbilt-Ingram has recently expanded its Phase I Drug Development Program with newly dedicated clinical space and new leadership. Jordan Berlin, M.D., associate professor of Medicine, will direct the program, and Igor Puzanov, M.D., assistant professor of Medicine, will serve as associate director.

In the Phase I Program, researchers test new anti- cancer compounds in a small group of people for the first time. They evaluate safety, determine dosage and identify side effects. Phase I trials are not usually designed to test drug effectiveness. But with the advent of targeted drugs and the ability to “tailor” these medicines to selected patients, it may be time to re-think some strategies of Phase I studies, Sosman says.

“I think we need to make the greatest effort to match the drugs to the tumor’s genetic changes – and perhaps even as early as in a Phase I trial.”

– by Leigh MacMillan

For more information about clinical trials at Vanderbilt-Ingram, please visit www.vicc.org/ct

The fabric of personalized cancer medicine

Scientists were still busy at work mapping the human genome back in 1997, when the creation of the Robert J. Kleberg, Jr. and Helen C. Kleberg Center for Cancer Genetics and Genomics was first announced.

Completion of that ambitious project was years away, but scientists at Vanderbilt-Ingram were already looking to answer the next question: what do all these genes actually do?

Today, with the help of the Kleberg Foundation, Vanderbilt-Ingram Cancer Center scientists are poised to take the next step in this journey: to leverage knowledge of the genetic and molecular drivers of cancer and technological advances in imaging and other disciplines to detect cancers early and to precisely match effective treatments to the patients in whom they will work best.

The new name for the center –the Robert J. Kleberg, Jr. and Helen C. Kleberg Center for Personalized Cancer Medicine – reflects not only groundwork of the foundation’s earlier support but the promise of future impact in cancer detection, treatment, prevention and survivorship care.

“We applaud Vanderbilt-Ingram Cancer Center’s groundbreaking research and their many successes, and we are pleased to expand our partnership with them in a way that can improve the lives of so many patients and families affected by a cancer diagnosis,” said Helen Alexander, vice president of the San Antonio-based foundation.

Such investment by private philanthropists is critical, says Jennifer Pietenpol, Ph.D., director of the Vanderbilt-Ingram Cancer Center. “In today’s climate, government and industry are more reluctant than ever to take big risks, but it will take risks to make the kinds of giant leaps in cancer detection and treatment that we all want to make and that the public rightly demands.”

Over the years, Kleberg Foundation support totaling more than $12 million has enabled Vanderbilt-Ingram to recruit some of the best and brightest and to accelerate analysis and correlation of molecular features of tumors with clinical outcome. Recent findings include identification of a gene signature that may help predict outcome in certain types of breast cancer and discovery of a new molecule that might be used to put the brakes on a common type of head and neck cancer.